119 research outputs found
Durable response to palbociclib and letrozole in ovarian cancer with CDKN2A loss.
Alterations of the Retinoblastoma (Rb) pathway are frequent in ovarian cancer, typically resulting from CDKN2A down-regulation, CCNE1 amplification, CCND1/2 amplification, and RB1 loss. However, bi-allelic CDKN2A mutation or homozygous deletion is a very rare event, concerning less than 5% of patients.Initial trials with palbociclib in serous ovarian cancer have shown very modest benefit in unselected patient populations, thus underlining the need for a biomarker predicting response. We report the case of a heavily pre-treated patient with a serous ovarian tumor harboring a homozygous deletion of the CDKN2A gene that derived significant, prolonged clinical benefit from palbociclib, a CDK4/6 oral inhibitor, with letrozole. Treatment with palbociclib and letrozole started on February 2018, with an ongoing response after 12 months.In conclusion, homozygous CDKN2A deletion is rare and could be used to predict response to CDK4/6 inhibitors in association with other genomic features. We encourage further trials in this direction
HCN emission from translucent gas and UV-illuminated cloud edges revealed by wide-field IRAM 30m maps of Orion B GMC: Revisiting its role as tracer of the dense gas reservoir for star formation
We present 5 deg^2 (~250 pc^2) HCN, HNC, HCO+, and CO J=1-0 maps of the Orion
B GMC, complemented with existing wide-field [CI] 492 GHz maps, as well as new
pointed observations of rotationally excited HCN, HNC, H13CN, and HN13C lines.
We detect anomalous HCN J=1-0 hyperfine structure line emission almost
everywhere in the cloud. About 70% of the total HCN J=1-0 luminosity arises
from gas at A_V < 8 mag. The HCN/CO J=1-0 line intensity ratio shows a bimodal
behavior with an inflection point at A_V < 3 mag typical of translucent gas and
UV-illuminated cloud edges. We find that most of the HCN J=1-0 emission arises
from extended gas with n(H2) < 10^4 cm^-3, even lower density gas if the
ionization fraction is > 10^-5 and electron excitation dominates. This result
explains the low-A_V branch of the HCN/CO J=1-0 intensity ratio distribution.
Indeed, the highest HCN/CO ratios (~0.1) at A_V < 3 mag correspond to regions
of high [CI] 492 GHz/CO J=1-0 intensity ratios (>1) characteristic of
low-density PDRs. Enhanced FUV radiation favors the formation and excitation of
HCN on large scales, not only in dense star-forming clumps. The low surface
brightness HCN and HCO+ J=1-0 emission scale with I_FIR (a proxy of the stellar
FUV radiation field) in a similar way. Together with CO J=1-0, these lines
respond to increasing I_FIR up to G0~20. On the other hand, the bright HCN
J=1-0 emission from dense gas in star-forming clumps weakly responds to I_FIR
once the FUV radiation field becomes too intense (G0>1500). The different power
law scalings (produced by different chemistries, densities, and line excitation
regimes) in a single but spatially resolved GMC resemble the variety of
Kennicutt-Schmidt law indexes found in galaxy averages. As a corollary for
extragalactic studies, we conclude that high HCN/CO J=1-0 line intensity ratios
do not always imply the presence of dense gas.Comment: accepted for publication in A&A. 24 pages, 18 figures, plus Appendix.
Abridged Abstract. English language not edite
Topological data analysis reveals genotype-phenotype relationships in primary ciliary dyskinesia
Background: Primary ciliary dyskinesia (PCD) is a heterogeneous inherited disorder caused by mutations in approximately 50 cilia-related genes. PCD genotype-phenotype relationships have mostly arisen from small case series because existing statistical approaches to investigate relationships have been unsuitable for rare diseases. /
Methods: We applied a topological data analysis (TDA) approach to investigate genotype-phenotype relationships in PCD. Data from separate training and validation cohorts included 396 genetically defined individuals carrying pathogenic variants in PCD genes. To develop the TDA models, twelve clinical and diagnostic variables were included. TDA-driven hypotheses were subsequently tested using traditional statistics. /
Results: Disease severity at diagnosis measured by FEV1 z-score was (i) significantly worse in individuals with CCDC39 mutations compared to other gene mutations and (ii) better in those with DNAH11 mutations; the latter also reported less neonatal respiratory distress. Patients without neonatal respiratory distress had better preserved FEV1 at diagnosis. Individuals with DNAH5 mutations were phenotypically diverse. Cilia ultrastructure and beat pattern defects correlated closely to specific causative gene groups, confirming these tests can be used to support a genetic diagnosis. /
Conclusions: This large scale multi-national study presents PCD as a syndrome with overlapping symptoms and variation in phenotype, according to genotype. TDA modelling confirmed genotype-phenotype relationships reported by smaller studies (e.g. FEV1 worse with CCDC39 mutations), and identified new relationships, including FEV1 preservation with DNAH11 mutations and diversity of severity with DNAH5 mutations
Infection control, genetic assessment of drug resistance and drug susceptibility testing in the current management of multidrug/extensively-resistant tuberculosis (M/XDR-TB) in Europe: A tuberculosis network European Trialsgroup (TBNET) study
Aim Europe has the highest documented caseload and greatest increase in multidrug and extensively drug-resistant tuberculosis (M/XDR-TB) of all World Health Organization (WHO) regions. This survey examines how recommendations for M/XDR-TB management are being implemented. Methods TBNET is a pan-European clinical research collaboration for tuberculosis. An email survey of TBNET members collected data in relation to infection control, access to molecular tests and basic microbiology with drug sensitivity testing. Results 68/105 responses gave valid information and were from countries within the WHO European Region. Inpatient beds matched demand, but single rooms with negative pressure were only available in low incidence countries; ultraviolet decontamination was used in 5 sites, all with >10 patients with M/XDR-TB per year. Molecular tests for mutations associated with rifampicin resistance were widely available (88%), even in lower income and especially in high incidence countries. Molecular tests for other first line and second line drugs were less accessible (76 and 52% respectively). A third of physicians considered that drug susceptibility results were delayed by > 2 months. Conclusion Infection control for inpatients with M/XDR-TB remains a problem in high incidence countries. Rifampicin resistance is readily detected, but tests to plan regimens tailored to the drug susceptibilities of the strain of Mycobacterium tuberculosis are significantly delayed, allowing for further drug resistance to develop
HCN emission from translucent gas and UV-illuminated cloud edges revealed by wide-field IRAM 30m maps of Orion B GMC: Revisiting its role as tracer of the dense gas reservoir for star formation
35 pags., 28 figs., 14 tabs.We present 5 deg^2 (~250 pc^2) HCN, HNC, HCO+, and CO J=1-0 maps of the Orion
B GMC, complemented with existing wide-field [CI] 492 GHz maps, as well as new
pointed observations of rotationally excited HCN, HNC, H13CN, and HN13C lines.
We detect anomalous HCN J=1-0 hyperfine structure line emission almost
everywhere in the cloud. About 70% of the total HCN J=1-0 luminosity arises
from gas at A_V < 8 mag. The HCN/CO J=1-0 line intensity ratio shows a bimodal
behavior with an inflection point at A_V < 3 mag typical of translucent gas and
UV-illuminated cloud edges. We find that most of the HCN J=1-0 emission arises
from extended gas with n(H2) ~< 10^4 cm^-3, even lower density gas if the
ionization fraction is > 10^-5 and electron excitation dominates. This result
explains the low-A_V branch of the HCN/CO J=1-0 intensity ratio distribution.
Indeed, the highest HCN/CO ratios (~0.1) at A_V < 3 mag correspond to regions
of high [CI] 492 GHz/CO J=1-0 intensity ratios (>1) characteristic of
low-density PDRs. Enhanced FUV radiation favors the formation and excitation of
HCN on large scales, not only in dense star-forming clumps. The low surface
brightness HCN and HCO+ J=1-0 emission scale with I_FIR (a proxy of the stellar
FUV radiation field) in a similar way. Together with CO J=1-0, these lines
respond to increasing I_FIR up to G0~20. On the other hand, the bright HCN
J=1-0 emission from dense gas in star-forming clumps weakly responds to I_FIR
once the FUV radiation field becomes too intense (G0>1500). The different power
law scalings (produced by different chemistries, densities, and line excitation
regimes) in a single but spatially resolved GMC resemble the variety of
Kennicutt-Schmidt law indexes found in galaxy averages. As a corollary for
extragalactic studies, we conclude that high HCN/CO J=1-0 line intensity ratios
do not always imply the presence of dense gas.M.G.S.M. and J.R.G. thank the Spanish MICINN for funding support under grant PID2019-106110GB-I00. This work was supported by the French Agence Nationale de la Recherche through the DAOISM grant ANR-21-CE31–0010, and by the Programme National “Physique et Chimie du Milieu Interstellaire”
(PCMI) of CNRS/INSU with INC/INP, co-funded by CEA and CNES. Part of this research was carried out at the Jet Propulsion Laboratory, California Institute
of Technology, under a contract with the National Aeronautics and Space Administration (80NM0018D0004).Peer reviewe
The disease-specific clinical trial network for primary ciliary dyskinesia: PCD-CTN
Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by impaired mucociliary clearance leading to irreversible lung damage. In contrast to other rare lung diseases like cystic fibrosis (CF), there are only few clinical trials and limited evidence-based treatments. Management is mainly based on expert opinions and treatment is challenging due to a wide range of clinical manifestations and disease severity. To improve clinical and translational research and facilitate development of new treatments, the clinical trial network for PCD (PCD-CTN) was founded in 2020 under the framework of the European Reference Network (ERN)-LUNG PCD Core. Applications from European PCD sites interested in participating in the PCD-CTN were requested. Inclusion criteria consisted of patient numbers, membership of ERN-LUNG PCD Core, use of associated standards of care, experience in PCD and/or CF clinical research, resources to run clinical trials, good clinical practice (GCP) certifications and institutional support. So far, applications from 22 trial sites in 18 European countries have been approved, including >1400 adult and >1600 paediatric individuals with PCD. The PCD-CTN is headed by a coordinating centre and consists of a steering and executive committee, a data safety monitoring board and committees for protocol review, training and standardisation. A strong association with patient organisations and industrial companies are further cornerstones. All participating trial sites agreed on a code of conduct. As CTNs from other diseases have demonstrated successfully, this newly formed PCD-CTN operates to establish evidence-based treatments for this orphan disease and to bring new personalised treatment approaches to patients
The disease-specific clinical trial network for primary ciliary dyskinesia: PCD-CTN
Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by impaired mucociliary clearance leading to irreversible lung damage. In contrast to other rare lung diseases like cystic fibrosis (CF), there are only few clinical trials and limited evidence-based treatments. Management is mainly based on expert opinions and treatment is challenging due to a wide range of clinical manifestations and disease severity. To improve clinical and translational research and facilitate development of new treatments, the clinical trial network for PCD (PCD-CTN) was founded in 2020 under the framework of the European Reference Network (ERN)-LUNG PCD Core. Applications from European PCD sites interested in participating in the PCD-CTN were requested. Inclusion criteria consisted of patient numbers, membership of ERN-LUNG PCD Core, use of associated standards of care, experience in PCD and/or CF clinical research, resources to run clinical trials, good clinical practice (GCP) certifications and institutional support. So far, applications from 22 trial sites in 18 European countries have been approved, including >1400 adult and >1600 paediatric individuals with PCD. The PCD-CTN is headed by a coordinating centre and consists of a steering and executive committee, a data safety monitoring board and committees for protocol review, training and standardisation. A strong association with patient organisations and industrial companies are further cornerstones. All participating trial sites agreed on a code of conduct. As CTNs from other diseases have demonstrated successfully, this newly formed PCD-CTN operates to establish evidence-based treatments for this orphan disease and to bring new personalised treatment approaches to patients
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